I have recently found that rats with knifecut lesions of all ascending catecholamine-containing pathways show increased locomotion after amphetamine treatment; and I have reason to believe that this effect may be due to an action of amphetamine on locus coeruleus (LC) norepinephrine-containing neurons. I will test this hypothesis by: a) determining whether animals with knifecut lesions and bilateral LC lesions show behavioral activation to amphetamine; b) determining whether electrical stimulation of the LC produces electrophysiological effects equivalent to those we have seen after amphetamine treatment, and whether bilateral elimination of the LC in animals with knifecuts blocks the electrophysiological effects produced by amphetamine. I have also found that the pretreatment of neonatal rats with 6-OHDA produces a behavioral inhibition after amphetamine. This suggests the presence of inhibitory systems activated by amphetamine. I will test whether cholinergic, serotonergic, or striatal dopaminergic systems contribute to this inhibitory effect by: a) determining whether scopolamine blocks the inhibition and by testing for amphetamine activation in 14-16-day-old rats (before cholinergic systems develop); b) determining whether PCPA blocks the inhibition; c) determining whether the inhibitory effect can be induced by intracerebral injections of 6-OHDA into the n. accumbens. The results of these studies should help to clarify the action of amphetamine, a frequently abused drug. I will elaborate the syndrome of the animal receiving 6-OHDA neonatally by: a) measuring activity longitudinally in photocell cages; b) testing emotionality (open field) and irritability (shock-elicited aggression); c) assessing learning deficits (using two-way avoidance and bar-pressing for food); d) testing the effects of phenobarbital and d-vs. 1- amphetamine. These studies should tell us whether this preparation will serve as an animal analog for minimal brain dysfunction.